The present invention relates to the treatment and prevention of benign breast diseases with 4-hydroxy tamoxifen (4-OHT).
Benign breast disease refers to a constellation of common non-malignant aberrations in breast tissue. These aberrations include numerous lesions that have well-defined histological characteristics, and can be classified as proliferative or nonproliferative. Notable examples include adenosis, cysts, duct ectasia, fibroadenoma, fibrocystic disease, fibrosis, hyperplasia and metaplasia. Because benign breast disease is estrogen-related, the affected population is mainly adult premenopausal women. In this population, benign breast disease can interfere with childbearing and contraception, and current treatment options can adversely affect patient quality of life.
Although benign breast disease rarely poses an immediate threat to a patient's health, it often causes persistent emotional anxiety and physical pain. In particular, benign lesions must be histologically evaluated to distinguish them from breast cancer. Such evaluations are expensive, time consuming, frequently invasive (e.g., repeated needle aspirations, biopsies and ductal lavage) and painful, and submit a patient to high amounts of emotional stress.
Additionally, numerous studies have demonstrated that women with a history of benign breast disease have an increased breast cancer risk (Dupont, 1985; Fitzgibbons, 1998; Carter 1988; and Krieger, 1992). The level of risk varies by type of benign lesion. For example, fibroadenoma increases the risk of invasive breast cancer 2.2 fold, adenosis increases the risk 3.7 fold, duct atypia increases the risk 3.9 fold and atypical hyperplasia increases the risk 5.3 fold (Dupont, 1985; Bodian, 1993; Dupont, 1994). The risk for developing breast cancer further increases when the presence of benign breast disease is combined with a family history of breast cancer. For instance, atypia combined with a family history of breast cancer increases a patient's risk for developing breast cancer 11 fold (Dupont, 1985).
Administration of the breast cancer drug tamoxifen significantly reduces the risk that a patient will develop benign breast disease (Tan-Chiu, 2003). In this regard, tamoxifen works by competitively binding to estrogen receptors, thereby blocking the effects of estrogen on breast cells. Overall, tamoxifen reduces the risk of developing benign breast disease by 28%, but the reduction varies according to disease type. One recent study reported statistically significant decreases of 41% for adenosis, 34% for cyst, 28% for duct ectasia, 33% for fibrocystic disease, 40% for hyperplasia and 49% for metaplasia. For women under 50, the administration of tamoxifen reduced by 41% the need for breast biopsies. The psychological and economic implications of such reductions are enormous.
In spite of its benefits, tamoxifen has significant drawbacks. Its action potentially impacts on every estrogen receptor-bearing cell in the body, and, as both an agonist and antagonist, tamoxifen provokes a wide range of systemic effects. These effects increase the risk of endometrial cancer and sarcoma, endometrial hyperplasia and polyps, ovarian cysts, deep vein thrombosis and pulmonary embolism, changes in liver enzyme levels and hepatic steatosis, hyperlipidemia, and ocular toxicities, including cataracts (Shushan, 1996; Nishino, 2003; Hoxumi, 1988). Intake of oral tamoxifen precludes pregnancy, even two months after stopping treatment, and precludes the use of hormonal contraception. Additionally, patients treated with oral tamoxifen report having hot flashes, vaginal discharge, depression, amenorrhea, and nausea (Ibis, 2002; Fentiman 1986, 1988, 1989).
A strong need, therefore, still exists for methods to treat and to prevent benign breast diseases without provoking significant adverse systemic side effects, particularly in the premenopausal population.